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      Targeting Notch signalling by the conserved miR-8/200 microRNA family in development and cancer cells

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          Targeting Notch signalling by the conserved miR-8/200 microRNA family in development and cancer cells

          A genetic screen in Drosophila uncovers miR-8 as an inhibitor of Notch-induced overgrowth, and identifies a conserved regulatory network comprising the Notch pathway, ZEB1 and this miRNA regulating metastasis and proliferation in flies and cancer cells. See also Brabletz et al in this issue.

          Abstract

          Notch signalling is crucial for the correct development and growth of numerous organs and tissues, and when subverted it can cause cancer. Loss of miR-8/200 microRNAs (miRNAs) is commonly observed in advanced tumours and correlates with their invasion and acquisition of stem-like properties. Here, we show that this miRNA family controls Notch signalling activation in Drosophila and human cells. In an overexpression screen, we identified the Drosophila miR-8 as a potent inhibitor of Notch-induced overgrowth and tumour metastasis. Gain and loss of mir-8 provoked developmental defects reminiscent of impaired Notch signalling and we demonstrated that miR-8 directly inhibits Notch ligand Serrate. Likewise, miR-200c and miR-141 directly inhibited JAGGED1, impeding proliferation of human metastatic prostate cancer cells. It has been suggested that JAGGED1 may also be important for metastases. Although in metastatic cancer cells, JAGGED1 modestly regulated ZEB1, the miR-200c's target in invasion, studies in Drosophila revealed that only concurrent overexpression of Notch and Zfh1/ ZEB1 induced tumour metastases. Together, these data define a new way to attenuate or boost Notch signalling that may have clinical interest.

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          Most cited references47

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          Epithelial-mesenchymal transitions in development and disease.

          The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
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            The canonical Notch signaling pathway: unfolding the activation mechanism.

            Notch signaling regulates many aspects of metazoan development and tissue renewal. Accordingly, the misregulation or loss of Notch signaling underlies a wide range of human disorders, from developmental syndromes to adult-onset diseases and cancer. Notch signaling is remarkably robust in most tissues even though each Notch molecule is irreversibly activated by proteolysis and signals only once without amplification by secondary messenger cascades. In this Review, we highlight recent studies in Notch signaling that reveal new molecular details about the regulation of ligand-mediated receptor activation, receptor proteolysis, and target selection.
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              Relief of microRNA-mediated translational repression in human cells subjected to stress.

              In metazoans, most microRNAs imperfectly base-pair with the 3' untranslated region (3'UTR) of target mRNAs and prevent protein accumulation by either repressing translation or inducing mRNA degradation. Examples of specific mRNAs undergoing microRNA-mediated repression are numerous, but whether the repression is a reversible process remains largely unknown. Here we show that cationic amino acid transporter 1 (CAT-1) mRNA and reporters bearing its 3'UTR can be relieved from the microRNA miR-122-induced inhibition in human hepatocarcinoma cells subjected to different stress conditions. The derepression of CAT-1 mRNA is accompanied by its release from cytoplasmic processing bodies and its recruitment to polysomes. The derepression requires binding of HuR, an AU-rich-element binding protein, to the 3'UTR of CAT-1 mRNA. We propose that proteins interacting with the 3'UTR will generally act as modifiers altering the potential of miRNAs to repress gene expression.
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                Author and article information

                Journal
                EMBO J
                The EMBO Journal
                Nature Publishing Group
                0261-4189
                1460-2075
                16 February 2011
                11 January 2011
                11 January 2011
                : 30
                : 4
                : 756-769
                Affiliations
                [1 ]simpleInstituto de Neurociencias, Consejo Superior de Investigaciones Científicas (CSIC) and Universidad Miguel Hernández (UMH), Campus de Sant Joan , Sant Joan, Alicante, Spain
                Author notes
                [a ]Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Miguel Hernández (UMH), Campus de Sant Joan, Apartado 18, Sant Joan, 03550 Alicante, Spain. Tel.: +34 96 591 9390; Fax: +34 96 591 9561; E-mail: m.dominguez@ 123456umh.es
                Article
                emboj2010358
                10.1038/emboj.2010.358
                3041954
                21224847
                55985aa5-6501-4e24-85f7-f1655cb6f090
                Copyright © 2011, European Molecular Biology Organization

                This is an open-access article distributed under the terms of the Creative Commons Attribution Noncommercial Share Alike 3.0 Unported License, which allows readers to alter, transform, or build upon the article and then distribute the resulting work under the same or similar license to this one. The work must be attributed back to the original author and commercial use is not permitted without specific permission.

                History
                : 02 July 2010
                : 20 December 2010
                Categories
                Article

                Molecular biology
                development,mir-200c,cancer,microrna mir-8,notch
                Molecular biology
                development, mir-200c, cancer, microrna mir-8, notch

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